Aqueous solution and the use thereof

ABSTRACT

A sterilizable aqueous solution with substantially physiological values of the pH, bicarbonate concentration and CO 2  partial pressure, as well as with metabolizable anions in the form of two separately stored single solutions, which are combined with one another prior to use and whereof one is a bicarbonate-free, acid solution and the other a bicarbonate-containing, alkaline solution, is characterized in that per liter of the finished solution obtained by combining the two single solutions, the acid single solution contains 7.3 mmole±3% of at least one metabolizable, organic acid and the alkaline single solution 19.1 mmole±3% of alkali bicarbonate and 6.1 mmole±3% of alkali carbonate.

Bicarbonate-containing dialysis, substitution or infusion liquids forhemodialysis, peritoneal dialysis, hemofiltration or infusion arealready known. Such bicarbonate-containing liquids lead to variousgalenic problems, particularly if they are not used immediately afterpreparation and are instead stored in containers.

Bicarbonate solutions are not stable, because there is always a riskthat CO₂ escapes from a bicarbonate solution and consequently thecomposition of the solution changes. Certain constituents of suchliquids, particularly glucose and amino acids, can only be sterilized orstored with acid pH-values in the range 5.0 to 5.5, because otherwisedenaturation and/or brown colouration occurs. However, to be usable,dialysis or infusion solutions must be sterilizable. For thecompensation of calcium losses, it is often necessary to supply calciumions to dialysis patients with the dialysis solution. However, suchcalcium ions cannot be brought together at an alkaline pH-value with thecarbonate ions, which can be formed from the bicarbonate, becauseotherwise insoluble calcium carbonate would precipitate.

EP-OS 161 471 discloses a two-chamber container for the storage andpreparation of a bicarbonate-containing dialysis, substitution orinfusion liquid, which is made from a special polymer, which separatesthe two chambers from one another in a liquid and gas-tight manner. Onechamber contains a bicarbonate-free acid solution and the other abicarbonate-containing alkaline solution. Prior to use the two chamberscan be interconnected for mixing the contents and by means of an outlettube the mixed solution can be supplied for its intended use.

However, the latter document does not describe the simultaneous use ofalkali carbonate and alkali bicarbonate. It is in fact expressly pointedout that one of the two alkali salts is to be used. The storagecontainer provided for such liquids is difficult and expensive tomanufacture, because it must be ensured that no CO₂ escapes, so that thecomposition of the bicarbonate-containing alkaline solution does notchange during storage.

The aqueous solutions described in EP-OS 161 471 do not havephysiological values of the pH, the bicarbonate concentration and theCO₂ partial pressure. The same applies with regards to the dialysissolutions described in EP-OS 277 868. The dialysis solutions used up tonow, particularly in continuous ambulatory peritoneal dialysis do nothave a physiological composition, but instead, for stability reasons,always an acid pH-value, such as in the range 5.2 to 5.5. Such aciddialysis solutions can lead to damage to the peritoneum, to irritationof the defence system of the body and to pain in the abdominal cavity.

DE-OS 3 514 346 discloses liquids, particularly for the calibration ofCO₂ analysis equipment, which in contact with the atmospheric air do notchange their overall CO₂ content and which contain certainconcentrations of alkali carbonate and alkali bicarbonate. However, inthe case of these solutions it is solely a question of obtaining aliquid with a CO₂ partial pressure, which corresponds to that ofatmospheric air, but no attempt is made to adjust physiological valuesof the acid--base status of said liquid.

The problem of the invention was to obtain a sterilizable, aqueoussolution with physiological values of the pH, bicarbonate concentrationand CO₂ partial pressure usable as a dialysis, substitution or infusionsolution and which can be stored in air, without requiring specialequipment for preventing a diffusing off or in of carbon dioxide.

According to the invention this problem is solved by an aqueoussolution, which contains metabolizable anions and which is in the formof two separately stored single solutions to be combined prior to use,whereof one is a bicarbonate-free, acid solution and the other abicarbonate-containing, alkaline solution, the aqueous solutionaccording to the invention being characterized in that per liter of thefinished solution obtained by combining the two single solutions, theacid single solution contains 7.3 mmole±3% of at least one metabolizableorganic acid and the alkaline single solution 19.1 mmole±3% alkalibicarbonate and 6.1 mmole±3% alkali carbonate.

Aqueous solutions according to the invention having such a compositioncan be stored in air, without having to be placed in special containerspreventing a diffusing off or in of CO₂. Thus, there is no need to useas storage containers either glass bottles or flasks, which in manycases are difficult to handle, or specially constructed gas-impermeablecontainers, such as are e.g. described in EP-OS 161 471. This advantageis e.g. particularly significant in the case of ambulatory peritonealdialysis, in which it is comfortable and advantageous for the patient tobe able to use a normal bag for the dialysis liquid and to beindependent of glass containers.

The solutions according to the invention are sterilizable, even if theycontain e.g. glucose or amino acids, because the acid, bicarbonate-freesolution has a pH-value of approximately 5, which prevents denaturationor brown colouration.

The preliminary research leading to the present invention revealed thatdialysis, substitution or infusion solutions are particularly suitableif their pH-value, bicarbonate concentration and CO₂ partial pressurecorresponds to the physiological blood plasma values. Thesephysiological values of the acid-base status are in the case of the pHvalue 7.40±0.05, for the bicarbonate concentration 24 mmole/l and forthe CO₂ partial pressure 40 mm Hg. If these values are obtained in anartificially prepared aqueous solution, then on using such solutions asa dialysis, substitution or infusion solution, it is ensured that thereis not overdosing or underdosing relative to the acid-base status andconsequently an alkalosis or acidosis is produced, that nohyperventilation or hypoventilation occurs with respect to the breathingof a patient and at the point of application when used as an infusionsolution there are no local reactions on the vein or when used as aperitoneal dialysis solution there are no local reactions on theperitoneum.

The inventive aqueous solutions quantitatively give said physiologicalvalues, so that the indicated advantages are obtained when using saidaqueous solutions.

The aqueous solutions according to the invention also permit theaddition of all possible desired electrolytes, such as calcium and/ormagnesium ions, without there being any risk of precipitating calcium ormagnesium carbonate, because these ions are added to thebicarbonate-free acid solution.

Metabolizable anions of organic acids are desired for the therapy ofacidosis. In the inventive aqueous solutions these anions constitutelong-term buffers, because their action is only observed after minutesto hours following administration, as a function of the reaction in thehepatic metabolism and as a function of the organic acid or acids used.

This long-term buffer effect supplements the immediate buffer effect ofthe bicarbonate in physiological concentration.

On combining the two single solutions, accompanied by the formation ofthe finished inventive solution, the metabolizable, organic acids of theacid single solution primarily quantitatively react with the carbonateions of the alkaline single solution, because the carbonate ions have ahigher pK than the bicarbonate ions. From the carbonate ions are formedbicarbonate ions, which only react in a secondary, quantitative mannerwith the remaining metabolizable organic acids, accompanied by theformation of CO₂ +H₂ O. This secondary reaction produces a CO₂ partialpressure of 40 mm Hg.

In particular the alkali carbonate, but also alkali bicarbonate are usedin the solution system according to the invention in order to form thealkali salts of the added, metabolizable organic acids, which isdecisive for the therapy. If the organism was in fact supplied with theorganic acid, such as e.g. lactic acid, the latter dissociatescompletely at the physiological pH of 7.40 and consequently leads toacidosis. If it is decomposed in the metabolism, such as in the liver,CO₂ +H₂ O are formed, i.e. neutral end products. In the case of lacticacid infusion, e.g. the pH-value immediately drops (acidosis) and isthen standardized within roughly 2 hours.

However, if the alkali salt, such as sodium lactate is added to theorganism, within minutes to hours and in accordance with the metabolismof the acid salt in the liver, there is an alkalization of the organism,because per mole of salt the alkali salt carries 1 mole H⁺ into themetabolism. In the case of a lactate infusion, e.g. the pH-valueinitially remains neutral and then e.g. within 2 hours passes into thealkaline range.

The speed at which a metabolizable anion leads to an alkalization of theorganism is dependent on the metabolic position of the liver, the natureof the anions supplied and the anion concentration.

Metabolizable, organic anions are added to the infusion solutions, inorder to prophylactically initiate an alkalization of the organism.Metabolizable, organic anions are also used in dialysis solutions, inorder to compensate the acidosis of the dialysis patient which increasesduring dialysis.

Up to now, for galenic reasons no infusion solution has containedbicarbonate, which must necessarily lead to a so-called dilutionacidosis, because per liter of solution the organism must make availablefrom its reserve 24 mmole of bicarbonate. This dilution acidosis can bedetected both in vitro and in vivo.

The solutions according to the invention offer the further advantagethat with respect to the metabolizable ions, whose alkalization effectis desired, no false dosing is possible, which can in turn lead to aniatrogenic alkalosis, which may represent a risk for the patient,because he must compensate this alkalosis by hypoventilation, which islimited because the reduction of breathing can produce a hypoxia (oxygendeficiency) on the part of the patient.

Thus, the inventive solutions contain the immediate buffer bicarbonatein physiological concentration, together with the long-term buffermetabolized anion in the desired concentration. Preferred metabolizableacids usable in the aqueous solutions according to the invention arepyruvic, lactic, oxalic, fumaric, acetic, malic, maleic, malonic andsuccinic acids.

It is also preferable to adjust the divergences of 7.3 mmole of themetabolizable acids, 19.1 mmole of the alkali bicarbonate and 6.1 mmoleof the alkali carbonate per liter of finished solution to only ±1%, inorder to obtain a pH-value of 7.40±0.05 and obtain divergences of theCO₂ partial pressure of ±4 mm Hg.

The above-indicated millimole quantitities for the individual componentsrelate to the volume of the finished solution obtained from the twosingle solutions by mixing, so that the volumes of the acid and alkalinesingle solutions can be varied at random, provided that theirconcentrations are adjusted in accordance with the above teaching. Ife.g. the acid and alkaline single solution is in each case adjusted to 1liter, so that the finished solution has a volume of 2 l, then in theacid solution it is necessary to have 14.6 mmole/l of the metabolizable,organic acid and in the alkaline solution 38.2 mmole/l of alkalibicarbonate and 12.2 mmole/l of alkali carbonate. On changing the volumeratios of the two single solutions the concentrations must becorrespondingly converted.

When the description and claims refers to an acid and alkaline singlesolution, this obviously also covers the possibility of the total volumeof the acid and alkaline single solution being subdivided, whichhowever, normally leads to no additional advantage. These partialquantities of the alkaline or acid single solution can be the same ordifferent with respect to the composition, provided that in all thepartial quantities of the single solutions together the above-indicatedmillimoles of the indicated components are obtained.

It is also appropriate for the acid single solution to additionallycontain calcium and magnesium ions. As stated, it can also additionallycontain other substances, such as glucose and/or amino acids.

The aqueous solutions according to the invention completely eliminatethe hitherto known problems of bicarbonate infusions. When administeringbicarbonate for the therapy of an acidosis CO₂ +H₂ O. The administrationof relatively high bicarbonate concentrations consequently always leadsto a hyperventilation, which is unpleasant for the patient, because thenecessarily formed CO₂ represents a breathing stimulus, which triggersthe hyperventilation, for the purpose of breathing the additionallyformed CO₂. As the inventive infusion solutions have a bicarbonateconcentration of 24 mmole/l, the overdosing or incorrect dosing ofbicarbonate in an infusion solution is automatically excluded.

The acid single dose can, in addition to the metabolizable organic acidor acids, also contain salts thereof, in order to obtain the desiredmetabolizable anion concentration.

The following tables I to III provide examples for the composition ofthe acid single solution in conjunction with the resulting baseconcentrations in the finished, combined solution following 1:1 mixingwith the alkaline solution, all the details relating to 37° C. and theconcentrations are given in millimole/liter.

                  TABLE I                                                         ______________________________________                                        Single solutions, pH = 4.0 to 6.0                                             Examples of the composition of the acid single solutions and the              base concentrations in the finished solutions (details based                  on 37° C., concentrations (c) in mmole/l)                                                          Finished                                                         Acid Single Solution                                                                       Solution                                          Acid    Base     pK      pH   cAcid cBase cBase                               ______________________________________                                        Lactic acid                                                                           Lactate  3.678   4.0  14.60 30.65 22.62                               Oxalic acid                                                                           Oxalate  3.846   4.0  14.60 20.82 17.71                               Fumaric Fumarate 4.166   4.0  14.60 9.96  12.28                               acid                                                                          Acetic acid                                                                           Acetate  4.565   4.0  14.60 3.99  9.29                                Malic acid                                                                            Malate   4.728   4.0  14.60 2.73  8.67                                Acetic acid                                                                           Acetate  4.655   5.0  14.60 39.76 27.18                               Malic acid                                                                            Malate   4.728   5.0  14.60 27.32 20.96                               Succinic                                                                              Succinate                                                                              5.307   5.0  14.60 7.20  10.90                               acid                                                                          Malonic Malonate 5.320   5.0  14.60 6.99  10.79                               acid                                                                          Maleic acid                                                                           Maleate  5.842   5.0  14.60 2.10  8.35                                Succinic                                                                              Succinate                                                                              5.307   6.0  14.60 72.00 43.30                               acid                                                                          Malonic Malonate 5.320   6.0  14.60 69.88 42.24                               acid                                                                          Maleic acid                                                                           Maleate  5.842   6.0  14.60 21.01 17.80                               ______________________________________                                         The pK values are measured values at 37° C. and an ionic strength      of 160 mmole/l.                                                          

Results:

1. As a function of the pH-setting of the acid solution, which takesplace for galenic reasons, only a limited number of organic acids can beused.

2. If the base concentration of the organic acid (metabolizable anion)is to be in a therapeutic range between approximately 10 and 50 mmole/l,based on the finished solution, only a limited pH-range can be used forthe acid single solution.

                  TABLE II                                                        ______________________________________                                        Combination solution, pH 5.0                                                  Example for the composition of the acid solution and the base                 concentrations in the finished solution, if several metabolizable             organic acids or their bases (anions) are to be combined (details             based on 37° C., concentration (c) in mmole/l)                                                     Finished                                                         Acid Single Solution                                                                       Solution                                          Acid    Base     pK      pH   cAcid cBase cBase                               ______________________________________                                        Fumaric Fumarate 4.166   5.0  4.867 33.21 19.04                               acid                                                                          Succinic                                                                              Succinate                                                                              5.307   5.0  4.867 2.40  3.63                                acid                                                                          Maleic  Maleate  5.842   5.0  4.857 0.70  2.78                                acid    Sum              5.0  14.60 36.31 25.45                               ______________________________________                                    

                  TABLE III                                                       ______________________________________                                        Single solutions with malonic acid/malonate, pH = 4.0 to 6.0                  Examples for the composition of the acid single solution and the              base concentrations in the finished solution, if the same                     metabolizable acid or its base (anion) is to be used at different             pH-values (details based on 37° C., concentration (c) in mmole/l)                                  Finished                                                         Acid Single Solution                                                                       Solution                                          Acid    Base     pK      pH   cAcid cBase cBase                               ______________________________________                                        Malonic Malonate 5.320   4.0  14.60 0.7   7.65                                acid                                                                          Malonic Malonate 5.320   5.0  14.60 6.99  10.79                               acid                                                                          Malonic Malonate 5.320   6.0  14.60 69.88 42.24                               acid                                                                          ______________________________________                                    

Measurement results

Measurement of the pH-value (mean value of 10 measurements, 37° C.)before and after mixing the alkaline single solution (HCO₃ ⁻ /CO₃ ⁻⁻)with the acid single solution (Na⁺, K⁺, Ca⁺⁺, organic acid, organicbase, Cl⁻) in a ratio of 1:1 with the aim of obtaining in the finishedsolution pH=7.40±0.05, cHCO₃ ³¹ =24.0 mmole/l, cNa⁺ =140 mmole/l, cK⁺=4.0 mmole/l, cCa⁺⁺ =2.5 mmole/l (as a function of the concentration ofthe organic acid/base, the NaCl concentration of the acid singlesolution must be correspondingly adjusted).

    ______________________________________                                                    Alkaline Acid                                                                 single   single   Finished                                                    solution solution solution                                        ______________________________________                                        Solutions according to table I with a pH of 5.0:                              Acetic acid/Acetate                                                                         9.38       5.07     7.407                                       Malic acid/Malate        4.93     7.395                                       Succinic acid/Succinate  5.06     7.393                                       Maleic acid/Maleate      4.92     7.409                                       Combination solution according to Table II:                                   Fumaric acid/Fumarate                                                         Succinic acid/Succinate                                                       Maleic acid/Maleate                                                                         9.39       4.99     7.401                                       Solutions according to Table III:                                             Malonic acid/Malonate                                                                       9.39       4.16     7.412                                       Malonic acid/Malonate    4.95     7.416                                       Malonic acid/Malonate    5.94     *7.519                                      ______________________________________                                         *Note                                                                         As the malonic acid has a relatively high pKvalue (5.32) at a pH of 7.40      it leads to a minimum buffer effect if present in high concentration (her     42.24 mmole/l): CO.sub.2 (H.sub.2 CO.sub.3) is buffered in traces, so tha     there was a minimum pHvalue rise (pCO.sub.2 dropped).                    

The invention also relates to the use of the above-described aqueoussolutions, particularly as dialysis, substitution or infusion solutions.

EXAMPLE

In the following performance example (details related to 37° C.), thealkaline single solution and acid single solution were in each caseadjusted to 1 liter. The alkaline single solution contained 38.2 mmole/lof sodium bicarbonate and 12.2 mmole/l of sodium carbonate and thepH-value of the solution was 9.4.

The acid single solution contained 14.6 mmole/l of acetic acid and 39.8mmole/l of sodium acetate and had a pH-value of 5.0.

Both solutions were completely stable in storage without using specialcontainers preventing a diffusing in or out of CO₂. Their compositionremained stable over long periods.

On combining the two single solutions 2 l, of finished solution wasobtained with a CO₂ partial pressure of 40 mm Hg, a pH-value of 7.40, abicarbonate concentration of 24.0 mmole/l and an acetate concentrationof 27.2 mmole/l. This solution can be used with advantage as a dialysis,substitution or infusion solution.

I claim:
 1. Sterilizable aqueous solution with substantiallyphysiological values of the pH, bicarbonate concentration and CO₂partial pressure, as well as with metabolizable anions in the form oftwo separately stored single solutions, which are combined with oneanother prior to use and whereof one is a bicarbonate-free, acidsolution that is storage stable in contact with atmospheric air and theother a bicarbonate-containing, alkaline solution that is also stable incontact with atmospheric air, characterized in that per liter of thefinished solution obtained by combining the two single solutions, theacid single solution contains 7.3 mmole±3% of at least onemetabolizable, organic acid and the alkaline single solution 19.1mmole±3% of alkali bicarbonate and 6.1 mmole±3% of alkali carbonate. 2.Solution according to claim 1, characterized in that, per liter of thefinished solution obtained by combining the two single solutions, theacid single solution contains 7.3 mmole±1% of metabolizable, organicacids and the alkaline single solution 19.1 mmole±1% of alkalibicarbonate and 6.1 mmole±1% of alkali carbonate.
 3. Solution accordingto claim 1, characterized in that the acid single solution additionallycontains at least one alkali salt of at least one metabolizable organicacid.
 4. Solution according to claim 3, characterized in that itcontains sodium salts of metabolizable, organic acids.
 5. Solutionaccording to any one of the claim 1, characterized in that it containsas the alkali bicarbonate sodium bicarbonate and as the alkali carbonatesodium carbonate.
 6. Solution according to claim 1, characterized inthat the acid single solution additionally contains calcium and/ormagnesium ions.
 7. Solution according to claim 1, characterized in thatit contains as metabolizable, organic acids pyruvic, lactic, oxalic,fumaric, acetic, succinic, malic, maleic and/or malonic acid.